利用分子筛选、生物物理研究和结合自由能计算从中药数据库中发现抗埃博拉病毒多靶点抑制剂。

Discovery of anti-Ebola virus multi-target inhibitors from traditional Chinese medicine database using molecular screening, biophysical investigation, and binding free energy calculations.

作者信息

Khan Abbas, Sayaf Abrar Mohammad, Mohammad Anwar, Alshabrmi Fahad M, Benameur Tarek, Wei Dong-Qing, Yeoh Kar Kheng, Agouni Abdelali

机构信息

Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; Division of Bioinformatics, Department of Biomedical Sciences, School of Medical and Life Sciences, Sunway University, 5, Jalan Universiti, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia.

School of Chemical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.

出版信息

J Infect Public Health. 2025 Feb;18(2):102636. doi: 10.1016/j.jiph.2024.102636. Epub 2024 Dec 30.

DOI:10.1016/j.jiph.2024.102636

PMID:39798213

Abstract

INTRODUCTION

Ebola virus (EBOV) is a highly lethal RNA virus that causes severe hemorrhagic fever in humans and non-human primates. The lack of effective treatment or vaccine for this pathogen poses a serious threat to a global pandemic. Therefore, it is imperative to explore new drugs and therapies to combat this life-threatening infection.

MATERIALS AND METHODS

In this study, we employed in silico methods to assess the inhibitory activity of natural products from traditional Chinese medicine (TCM) against four EBOV proteins that are crucial for viral replication and assembly: VP40, VP35, VP30, and VP24. We performed molecular docking of TCM compounds with the EBOV proteins and screened them based on their docking scores, binding free energies, and pharmacokinetic properties.

RESULTS

Our results pinpointed eight TCM compounds (TCM1797, TCM2872, TCM250, TCM2837, TCM2644, TCM4697, TCM2322, and TCM277) that exhibited superior efficacy in inhibiting all the EBOV proteins compared to the controls. These compounds interacted with key residues of the EBOV proteins through various types of bonds, such as hydrogen bonds, salt bridges, and π-π interactions, forming stable complexes that could disrupt the function of the EBOV proteins. These compounds were found to possess known antiviral activity, acceptable pharmacokinetic properties, and human usage history, which make them promising candidates for anti-EBOV drug development. Moreover, the molecular simulation analysis confirmed the binding stability, structural compactness, and residue flexibility properties of these compounds. Furthermore, the binding free energy results revealed that VP30-TCM2644, VP30-TCM4697, VP35-TCM2837, VP24-TCM250, and VP24-TCM277 complexes exhibit significant binding free energy values compared to the control ligands. Principal Component Analysis (PCA) and Free Energy Landscape (FEL) results revealed the trajectories' motion and conformational energy states.

CONCLUSIONS

Our findings provide valuable insights into the molecular mechanisms driving the efficacy of TCM drugs against EBOV and suggest novel approaches for the development of anti-EBOV therapies.

摘要

引言

埃博拉病毒（EBOV）是一种高致死性RNA病毒，可导致人类和非人类灵长类动物患上严重出血热。针对这种病原体缺乏有效的治疗方法或疫苗，对全球大流行构成了严重威胁。因此，探索新的药物和疗法来对抗这种危及生命的感染势在必行。

材料与方法

在本研究中，我们采用计算机模拟方法评估中药天然产物对病毒复制和组装至关重要的四种埃博拉病毒蛋白（VP40、VP35、VP30和VP24）的抑制活性。我们对中药化合物与埃博拉病毒蛋白进行了分子对接，并根据对接分数、结合自由能和药代动力学性质对它们进行筛选。

结果

我们的结果确定了八种中药化合物（TCM1797、TCM2872、TCM250、TCM2837、TCM2644、TCM4697、TCM2322和TCM277），与对照相比，它们在抑制所有埃博拉病毒蛋白方面表现出更高的功效。这些化合物通过氢键、盐桥和π-π相互作用等各种类型的键与埃博拉病毒蛋白的关键残基相互作用，形成稳定的复合物，可能会破坏埃博拉病毒蛋白的功能。发现这些化合物具有已知的抗病毒活性、可接受的药代动力学性质和人类使用历史，这使它们成为抗埃博拉病毒药物开发的有前途的候选物。此外，分子模拟分析证实了这些化合物的结合稳定性、结构紧凑性和残基灵活性性质。此外，结合自由能结果表明，与对照配体相比，VP30-TCM2644、VP30-TCM4697、VP35-TCM2837、VP24-TCM250和VP24-TCM277复合物表现出显著的结合自由能值。主成分分析（PCA）和自由能景观（FEL）结果揭示了轨迹的运动和构象能量状态。